Pentaerithrityl tetranitrate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

metabolism

GLP compliance:

not specified

Species:

human

Remarks:

Doses / Concentrations:20 mg, 40 mg

Details on excretion:

Formation of pentaerythritol mononitrate; Ratio pentaerythritol mononitrate: pentaerythritol excreted by urine:- Dose=40mg: 3:1- Dose=40 mg: 1:1

Metabolites identified:

yes

Details on metabolites:

Formation of pentaerythritol mononitrate.

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

metabolism

GLP compliance:

not specified

Species:

human

Remarks:

Doses / Concentrations:No data

Details on excretion:

Pentaerythritol and the mononitrate ester; unchanged drug were excreted by feces. only, Intestinal microflora would induced partial hydrolysis before absortion.

Metabolites identified:

yes

Details on metabolites:

Formation of pentaerythritol mononitrate ester.

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Species:

human

Remarks:

Doses / Concentrations:No data

Preliminary studies:

Significant blood levels of pentaerythritol dinitrate were found.

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Remarks:

Doses / Concentrations:No data

Details on absorption:

PETN is absorbed slowly from the gastrointestinal tract and lung but not through the skin

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Species:

other: no data

Remarks:

Doses / Concentrations:20 mg, 40 mg

Details on absorption:

Absorption of 60% and 50%, respectively. Hemodynamic effects begin after 20-60 min and last 4-5 hr

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 6

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Species:

other: no data

Remarks:

Doses / Concentrations:No data

Preliminary studies:

Pentaerythritol tetranitrate is absorbed from the gastrointestinal tract and from the oral mucosa. It may also be absorbed by undamaged skin

Details on absorption:

Pentaerythritol tetranitrate is absorbed from the gastrointestinal tract and from the oral mucosa. It may also be absorbed by undamaged skin

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 7

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Species:

human

Remarks:

Doses / Concentrations:20 mg, 40 mg (radioactive PETN)

No. of animals per sex per dose / concentration:

15

Preliminary studies:

Radioactivity was detected in the blood after 15 minutes.The tetranitrate and trinitrate were not detected in the blood.

Details on excretion:

Elimination via feces: Of the 20 mg and 40 mg doses 32 and 41% respectively.Elimination via urine: 60% of the 20 mg dose and 50% of the 40 mg dose were recovered in the urine in 48 hours

Metabolites identified:

yes

Details on metabolites:

pentaerythritol and pentaerythritol mononitrate were the principal metabolites.

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 8

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

GLP compliance:

not specified

Species:

other: no data

Route of administration:

oral: capsule

Remarks:

Doses / Concentrations:20 mg, 40 mg

Details on absorption:

60% of 20mg and 50% of 40 mg were absorbed. Hemodynamic effects start after 20-60 minutes and lasted 4-5 hours

Details on excretion:

It is excreted in urine and feces.

Metabolites identified:

yes

Details on metabolites:

These metabolites undergo glucuonide conjugation. Half-life of pentaerythriitol trinitrate is 10 minutes and it is therapeutically active.

Metabolites identified: pentaerythritol mononitrate, pentaerythritol dinitrate, pentaerythritol trinitrate and pentaerythritol.

Conclusions:

Interpretation of results: low bioaccumulation potential based on study resultsIt is pharmacologically active. It is used for the long-term prophylactic management of angina pectoris.

Reference 9

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

GLP compliance:

not specified

Species:

dog

Strain:

Beagle

Sex:

male

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

drinking water

Duration and frequency of treatment / exposure:

1 day

Details on absorption:

Slow absorption due to low water solubility

Details on distribution in tissues:

No data

Details on excretion:

No data

Test no.:

#1

Toxicokinetic parameters:

AUC: 252 mg x h/ml

Metabolites identified:

yes

Details on metabolites:

Concentration of pentaerythritol mononitrate in plasma increased significantly

Metabolites identified: Pentaerythritol mononitrate

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 10

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

GLP compliance:

not specified

Species:

human

Sex:

male

Route of administration:

oral: drinking water

Vehicle:

water

Duration and frequency of treatment / exposure:

1 day

No. of animals per sex per dose / concentration:

10 men

Control animals:

no

Details on absorption:

Slow absorption due to low water solubility

Details on distribution in tissues:

No data

Details on excretion:

No data

Test no.:

#1

Toxicokinetic parameters:

AUC: 31.5 mg x h/ml

Metabolites identified:

yes

Details on metabolites:

Concentration of pentaerythritol mononitrate in plasma increased significantly

Metabolites identified: Pentaerythritol mononitrate

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

Reference 11

Endpoint:

basic toxicokinetics, other

Type of information:

other: Collection of data - Absorption

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

Executive summary:

Von Oettingen et al. (1944) administered PETN by gavage with a tenfold excess of starch in a 10% gum arabic solution (PETN concentration, 20 mg/ml) to young female albino rats. Six hours later, the entire gastrointestinal tract was isolated, and only 13% of the PETN had been absorbed.

PETN was also mixed with acetone and rubbed onto the palm of a human hand; after 1 hour, essentially all of the PETN could be recovered by washing. In contrast, PETN was absorbed after insufflation of 100 mg into the lower trachea of dogs. The resulting decrease in blood pressure peaked at about 90 minutes.

DiCarlo et al. (1967a) studied the absorption of [14C]PETN from four ligated sections of the gastrointestinal tract in female Wistar rats. Absorption from the stomach was slow, and PETN was stable in stomach acid. Absorption was rapid from the small intestine and somewhat slower from the large intestine. Although the drug remaining in the small intestine was unchanged, bacterial action appeared to cause denitration in the large intestine, resulting in the uptake of the denitrated metabolites.

Studies in humans have indicated absorption of at least 60% of an oral dose of [14C]PETN. Label appeared in the blood within 15 minutes, but only the mono-and dinitrated forms were found (Davidson et al., 1970).

Reference 12

Endpoint:

basic toxicokinetics, other

Type of information:

other: Collection of data - Metabolism and excretion

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Executive summary:

DiCarlo et al. (1967d) administered [14C]PETN (10 mg/kg) by gavage to female Wistar rats. Approximately 8% of the radiolabel was absorbed during the first hour, 14% after 2 hours, 24% after 4 hours, and 60% after 18 hours. Radioactivity was first found in feces after 2 hours, and 10% of the dose was eliminated by this route after 18 hours. Most of the radioactivity absorbed during the first hour was cleared from blood and found in tissues, primarily fat and carcass. Pentaerythritol was determined to be the major final metabolite in rats.

PETN binds to both plasma proteins and erythrocytes, and denitration reactions (the major metabolic pathway) occur in vitro with both blood components, primarily with erythrocytes. Denitration reactions appear to be most rapid with the more highly nitrated metabolites, resulting in accumulation of the mono-and dinitrated forms (DiCarlo et al., 1965). Denitration reactions can be catalyzed by subcellular fractions of heart (DiCarlo et al., 1967b) and by liver parenchymal and reticuloendothelial cells (DiCarlo et al., 1967c; Melgar et al., 1974). The reaction requires reduced glutathione and a rather nonspecific enzyme termed glutathioneorganic nitrate reductase (Needleman and Hunter, 1965). Removal of one or more nitro groups allows the resulting alcohol to form glucuronide conjugates. The conjugates of pentaerythritol mono-, di-, and trinitrate were isolated from the bile ofWistar rats given [14C]pentaerythritol trinitrate by intravenous injection (Crew et al., 1971).

Little or no carbon dioxide results from PETN metabolism (Crew et aL, 1966). Most of the absorbed PETN is excreted in urine. Pentaerythritol di-and mononitrate and pentaerythritol were found in the urine in different proportions, depending on the time after administration. Crew et al. (1971) found that urinary excretion of the radiolabel was reduced by 60% in biliary cannulated Wistar rats compared with noncannulated rats that had received [14C]pentaerythritol trinitrate. This suggests that glucuronidated metabolites normally undergo enterohepatic circulation through reabsorption from the intestine after removal of glucuronic acid. Studies of metabolism patterns in mice have indicated a basic similarity to those of rats (Litchfield, 1971).

A quantitative study of the pharmacokinetics of PETN after oral or intra-arterial dosing in Sprague Dawley rats was performed by King and Fung (1986). PETN appeared to be rapidly converted to the denitrated metabolites after oral or intra-arterial administration, and only the di-or mononitrated metabolites were detected after oral dosing. The half-life of PETN in blood was 5.8 minutes, and that of the trinitrate and dinitrate was about 62 minutes each. The clearance of total label was 620 ml/minute per kilogram, which exceeds the cardiac output by about one-third and exceeds the denitrating capacity of blood plasma and erythrocytes. To account for this, King and Fung proposed that PETN and its metabolites are extracted from blood by the blood vessels.

Predominant forms in the urine were the mononitrate and the completely denitrated pentaerythritol. These results are similar to those observed for rats. In vitro studies with human blood have indicated a capability to degrade PETN primarily to the trinitrate but no further (King and Fung, 1985). The half-life for denitration of PETN in human blood was three to four times slower than that in rat blood. Studies of the in vivo pharmacodynamics of pentaerythritol trinitrate indicated that it was metabolized to pentaerythritol dinitrate and pentaerythritol mononitrate within a few minutes; the elimination half-life of pentaerythritol dinitrate from human blood was 10.5 hours, and that of pentaerythritol mononitrate was 7.3 hours (Davidson et al., 1971). Taken together, these results suggest a major role in humans for the absorption of the trinitrate following bacterial denitration of PETN in the intestine. However, the studies of Carter and Goldman (1976) have shown no evidence for the involvement of intestinal microflora in the absorption of PETN in the rat.

Reference 13

Endpoint:

dermal absorption, other

Type of information:

other: Collection of data

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Executive summary:

PETN was mixed with acetone and rubbed onto the palm of a human hand; after 1 hour, essentially all of the PETN could be recovered by washing [Von Oettingen et al. (1944)].

Description of key information

Pentaerythrytol tetranitrate is pharmacologically active when metabolised. It is transformed into pentaerythritol trinitrate, dinitrate and mononitrate, which are no longer pharmacologically active.

It is expected that PETN is absorbed slowly from the gastrointestinal tract and lung but not appreciably through the skin.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Pentaerythritol tetranitrate is metabolized primarily to pentaerythritol trinitrate, then to pentaerythritol dinitrate and finally the mononitrate. The trinitrate, dinitrate, and mononitrate metabolites may undergo glucuronide conjugation. The plasma half-life of pentaerythritol trinitrate, which is therapeutically active, is about 10 min. The other metabolites are inactive.